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Deciphering ExPEC Virulence Mechanisms

破译 ExPEC 毒力机制

基本信息

批准号：
8225132
负责人：
MATTHEW A MULVEY
金额：
$ 18.81万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225132
关键词：
Affect Antibiotic Resistance Bacteria Bacterial Proteins Biological Assay Biological Models Blood Blood Circulation Coupled Data Development Disease Elderly Embryo Environment Epidemiologic Studies Focal Infection Gene Expression Profiling Genes Genetic Genetic Screening Genomics Goals Growth Health Healthcare Immune response Immunocompromised Host In Situ Hybridization Incentives Individual Infection Longevity Medical Meningitis Microbe Modeling Mutagenesis Pathway interactions Pericardial body location Pericardial cavity Play Prevalence Prevention Publishing Quality of life Reporter Research Reverse Transcriptase Polymerase Chain Reaction Role Screening procedure Specificity Systemic infection Technology Time Treatment Protocols United States Urinary tract infection Virulence Virulence Factors Work Zebrafish cost fitness improved knockout gene microbial mutant neonatal sepsis next generation novel pathogen pathogenic Escherichia coli public health relevance tool

项目摘要

DESCRIPTION (provided by applicant): Extraintestinal pathogenic Escherichia coli (ExPEC) cause a diverse array of diseases including urinary tract infections, sepsis, and neonatal meningitis. These infections affect 6.7 to 8.6 million individuals each year in the United States, at a cost of $1.5 to $2.3 billion. Current treatment protocols for ExPEC-induced infections are often ineffective or rendered useless by the acquisition of antibiotic resistance. Genomic sequencing of several ExPEC isolates, in addition to epidemiological studies and genetic screens have identified numerous putative virulence factors. However, in most cases the functional roles of these bacterial factors during infection remain enigmatic. Recently, we have developed a novel infection model employing zebrafish embryos that allows for large-scale screening and functional analysis of ExPEC virulence mechanisms following bacterial inoculation into either the blood or pericardial chamber. An initial screen of several sequenced ExPEC isolates in this model system demonstrated that the virulence potential of these microbes can vary significantly in a niche-dependent fashion. These data suggest that ExPEC isolates have evolved multiple, probably overlapping strategies for enhanced survival and growth within specific host environments. Here we propose to utilize the zebrafish model system, in association with genetic screens and gene expression profiling, to delineate ExPEC virulence factors and host response pathways that come into play during both localized and systemic infections. The ultimate goal of the proposed research is to identify microbial targets that will aid the development of improved tools for the prevention and treatment of ExPEC-induced infections. If successful, this work has the potential to impact the quality of life, health, and longevity of millions. The emerging prevalence of antibiotic resistance among ExPEC isolates, as well as growing numbers of highly susceptible elderly and immunocompromised individuals, provide additional incentive for advancing our understanding of the myriad strengths and weaknesses of ExPEC. PUBLIC HEALTH RELEVANCE: Strains of Extraintestinal pathogenic Escherichia coli (ExPEC) cause a diverse array of serious illnesses that affect several million individuals each year, costing billions in health care and time loss at work. Using a novel zebrafish infection model, we propose to identify bacterial factors and host responses that modulate the ability of different ExPEC strains to cause disease during both systemic and localized infections.

描述（由申请方提供）：肠外致病性大肠杆菌（ExPEC）可引起多种疾病，包括尿路感染、败血症和新生儿脑膜炎。在美国，这些感染每年影响670万至860万人，成本为15亿至23亿美元。目前用于ExPEC诱导的感染的治疗方案通常是无效的或由于获得抗生素耐药性而变得无用。除了流行病学研究和遗传筛选外，几种ExPEC分离株的基因组测序已经确定了许多推定的毒力因子。然而，在大多数情况下，这些细菌因子在感染过程中的功能作用仍然是个谜。最近，我们开发了一种新的感染模型，采用斑马鱼胚胎，允许大规模筛选和功能分析的ExPEC毒力机制后，细菌接种到血液或心包腔。在该模型系统中对几种测序的ExPEC分离株进行的初步筛选表明，这些微生物的毒力潜力可以以生态位依赖的方式显着变化。这些数据表明，ExPEC分离株已经进化出多种可能重叠的策略，以增强特定宿主环境中的存活和生长。在这里，我们建议利用斑马鱼模型系统，与遗传筛选和基因表达谱，描绘ExPEC毒力因子和宿主反应途径，在局部和全身感染过程中发挥作用。拟议研究的最终目标是确定微生物目标，这将有助于开发用于预防和治疗ExPEC诱导的感染的改进工具。如果成功，这项工作有可能影响数百万人的生活质量、健康和寿命。ExPEC分离株中抗生素耐药性的流行，以及越来越多的高度易感老年人和免疫功能低下的个体，为我们进一步了解ExPEC的众多优点和缺点提供了额外的激励。公共卫生相关性：肠外致病性大肠杆菌（ExPEC）菌株导致各种严重疾病，每年影响数百万人，花费数十亿美元的医疗保健和工作时间损失。使用一种新的斑马鱼感染模型，我们建议确定细菌因子和宿主反应，调节不同的ExPEC菌株的能力，在全身和局部感染引起疾病。